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Addison's Disease

NORD is very grateful to Maria I. New, MD, Professor of Pediatrics and Human Genetics and Director of Adrenal Steroid Disorders Program, Mount Sinai School of Medicine, for assistance in the preparation of this report.

Synonyms of Addison's Disease

chronic adrenocortical insufficiency

primary adrenal insufficiency

primary failure adrenocortical insufficiency

Disorder Subdivisions

No subdivisions found.

General Discussion

Addison's disease is a rare disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the outer layer of cells of the adrenal glands (adrenal cortex). The symptoms of classic Addison's disease, also known as primary adrenal insufficiency, result from the insufficient production of these two hormones. Major symptoms include fatigue, gastrointestinal abnormalities, and changes in skin color (pigmentation). Behavior and mood changes may also occur in some individuals with Addison's disease. Increased excretion of water and low blood pressure (hypotension) can lead to extremely low concentrations of water in the body (dehydration). The symptoms of Addison's usually develop slowly, but sometimes can develop rapidly, a serious condition called acute adrenal failure. In most cases, Addison's disease occurs when the body's immune system mistakenly attacks the adrenal glands causing slowly progressive damage to the adrenal cortex.

Symptoms

The symptoms of Addison's disease can vary from one individual to another. Symptoms usually develop slowly over time and are usually vague and common to many conditions (nonspecific). This often leads to delays in the proper diagnosis of Addison's disease. In rare cases, the symptoms of Addison's disease can develop rapidly causing a condition called acute adrenal failure.

A common initial symptom of Addison's disease is the development of patches of skin that are darker than the surrounding skin (hyperpigmentation). This discoloration most commonly occurs near scars, by skin creases such as the knuckles, and on the mucous membranes such as the gums. Skin abnormalities can precede the development of other symptoms by months or years, but do not occur in every person.

Some individuals with Addison's disease may also develop a condition called vitiligo in which white patches may appear on different areas of the body. This may vary from one or two small spots on the skin or multiple, larger affected areas. Black freckles may develop on the forehead, face or shoulders in some cases.

A variety of gastrointestinal symptoms may be present including nausea, vomiting, and abdominal pain. Diarrhea is less common, but may also occur. Affected individuals may have a poor appetite and unintentional weight loss and may develop progressive fatigue and muscle weakness. Muscle pain (myalgia), muscle spasms and joint pain may also occur. Dehydration can also affect individuals with Addison's disease.

An additional symptom that may occur is low blood pressure (hypotension), which can cause lightheadedness or dizziness upon standing. Temporary loss of consciousness (syncope) can occur in some cases. Addison's disease can also lead to changes in emotion and behavior. The disorder has been associated with irritability, depression, and poor concentration.

Individuals with Addison's disease may have cravings for salt or salty foods and low blood sugar (glucose) levels. Women with Addison's disease may have irregular menstrual periods, lose body hair and have a decreased sexual drive.

In some cases, symptoms of Addison's disease may appear suddenly, a condition called acute adrenal failure or an addisonian crisis. During an addisonian crisis, affected individuals may develop a sudden loss of strength; severe pain in the lower back, abdomen or legs; vomiting and diarrhea potentially causing dehydration; and low blood pressure and loss of consciousness. An addisonian crisis is a medical emergency that can cause life-threatening complications such as shock or kidney failure if not treated. A crisis is usually set off when affected individuals are under stress such as during an accident, trauma, surgery or severe infection.

Causes

Most cases of Addison's disease occur due to damage or destruction of the adrenal cortex, the outermost layer of the adrenal glands. Symptoms usually do not develop until 90 percent of the adrenal cortex has been damaged.

When Addison's disease is caused by the inability of the adrenal cortex to produce hormones such as cortisol and aldosterone, it is referred to as primary adrenal insufficiency. When the adrenal glands are undamaged, but cannot produce these hormones for other reasons such as due to abnormalities of the pituitary gland, the condition is referred to as secondary adrenal insufficiency (For more information on secondary adrenal insufficiency see the Related Disorders section below).

In approximately 75 percent of cases of Addison's disease (primary adrenal insufficiency), damage to the adrenal cortex results from an autoimmune reaction. For reasons not completely understood, the body's natural immune defenses (antibodies, lymphocytes, etc.) mistakenly attack healthy tissue, in this case healthy cells of the adrenal gland. Autoimmune Addison's disease may occur by itself (as an isolated condition) or as part of a large disorder specifically the autoimmune polyendocrine syndromes I (APS type-1) and II (Schmidt syndrome).

In the past, tuberculosis was the major cause of Addison's disease and still remains a major cause of the disorder in developing countries. Less common causes of Addison's disease include repeated infections especially fungal infections, the spread of cancer from another area of the body to the adrenal glands, bleeding (hemorrhaging) into the adrenal gland, and the abnormal accumulation of a fatty-like substance with the adrenals (amyloidosis). (For more information on these disorders, choose "tuberculosis" and/or "amyloidosis" as your search terms in the Rare Disease Database.)

Addison's disease occurs due to failure of the adrenal glands to produce sufficient amounts of the hormones, cortisol and aldosterone. Hormones are chemicals produced by glands that control and regulate certain activities of cells or organs of the body. The characteristic symptoms of Addison's disease result from low levels of cortisol and aldosterone in the body.

Cortisol affects how the body responds to stress and is released in greater quantities when a person is under stress. Cortisol has many additional functions in the body including helping to maintain blood pressure and cardiovascular function, helping to regulate the amount of water in the body, playing a role in controlling blood sugar levels by balancing the effects of insulin and assisting in proper immune system function and in the breakdown (metabolism) of carbohydrates, fats and proteins.

Aldosterone affects the sodium and potassium ion equilibrium (electrolyte imbalance) in the body, as well as helping to maintain water levels and, therefore, blood pressure and blood volume. Deficiency of aldosterone hinders the kidney's ability to filter salt and water, resulting in low blood pressure.

The adrenal glands also produce androgen, a steroid hormone that controls the development of certain secondary sexual characteristics such as hair growth. Deficiency of androgen can cause loss of body hair and diminished sex drive in women. In males, androgen is primarily produced in the testes.

In rare cases, Addison's disease has run in families suggesting that, in these cases, individuals may have a genetic predisposition to developing the disorder. A genetic predisposition means that a person may carry a gene or gene(s) for a disease but the disease may not be expressed unless other factors (such as something in the environment) trigger the disease.

Affected Populations

Addison's disease affects males and females in equal numbers. Approximately 1 in 100,000 people in United States have Addison's disease. The overall prevalence is estimated to be between 40 and 60 people per million of the general population. Because cases of Addison's disease may go undiagnosed, it is difficult to determine its true frequency in the general population. Addison's disease can potentially affect individuals of any age, but usually occurs in individuals between 30-50 years of age. Addison's disease was first identified in the medical literature in 1855 by a physician named Thomas Addison.

Related Disorders

Symptoms of the following disorders can be similar to those of Addison's disease. Comparisons may be useful for a differential diagnosis.

ACTH deficiency is a rare disorder that arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. It is a form of secondary adrenal insufficiency. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to unintentional weight loss, lack of appetite, weakness, nausea, vomiting, and low blood pressure (hypotension). ACTH deficiency is a disorder that usually starts during adulthood, although a few cases have begun during childhood. Low blood levels of sugar and sodium and high potassium levels (hypoglycemia, hyponatremia and hyperkalemia) also occur. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Some adrenal hormones that are decreased include cortisol and aldosterone. Hormones that are precursors of male sex hormones known as "androgens" may also be reduced. Although males with this disorder usually have a normal hair pattern, females have very little pubic and underarm (axillary) hair. In contrast to Addison's disease, skin pigmentation usually remains normal. Emotional and behavioral changes may occur as well. (For more information on this disorder, choose "ACTH deficiency" as your search term in the Rare Disease Database.)

Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged. The adrenal gland produces "male" sex hormones (androgens) in both males and females because these are overproduced in certain forms of CAH. The external genitals of some females with this disorder become masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances which may be life threatening. (For more information on this disorder, choose "Adrenal Hyperplasia" as your search term in the Rare Disease Database.)

Adrenoleukodystrophy is an X-linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome. This condition affects the white matter of the nervous system and the adrenal cortex. Some affected individuals have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. Some of those affected experience serious neurological problems that can affect mental function and lead to disability and reduced life span. This condition has been categorized into six types based on symptoms and age of onset: childhood cerebral ALD, adolescent cerebral ALD, adrenomyeloneuropathy, adult cerebral ALD, adrenal insufficiency only and ALD that occurs in females.(For more information on this disorder, choose "adrenoleukodystrophy" as your search term in the Rare Disease Database.)

Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, is a rare autoimmune disorder in which there is a steep drop in production of several essential hormones by the glands that secrete these hormones. When first described, this disorder was thought to involve only adrenal insufficiency (Addison's disease) and thyroid insufficiency (Hashimoto's thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically. Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse. Most cases of this disorder are sporadic although some clinical researchers believe that there is a familial or hereditary trait associated with AIPS-II. If so, it may involve a complex interaction among many genes. (For more information on this disorder, choose "Schmidt syndrome" as your search term in the Rare Disease Database.)

Autoimmune polyendocrine syndrome type I, (APS type 1) also known as APECED syndrome, is a rare genetic syndrome involving the autoimmune system. It is a combination of several distinct disorders and is defined as the subnormal functioning of several endocrine glands at the same time (concurrently). The acronym APECED stands for Autoimmune Polyendocrinopathy (APE), Candidiasis (C) and Ectodermal Dysplasia (ED). Autoimmune disease affecting one gland is frequently followed by the impairment of other glands. In this syndrome two major patterns of failure have been described. Beginning in childhood, yeast infections of either the mouth or nails are usually one of the first apparent symptoms of APS type-. Low plasma levels of calcium and phosphate (hypoparathyroidism) are often diagnosed before adrenal dystrophy. There may be an inability to adequately absorb nutrients with resulting diarrhea. Anemia, autoimmune thyroid disease, and loss or delay of sexual development may also occur. The combination of ectodermal dysplasia with candidiasis or hypoparathyroidism may also indicate an APS type-1 patient. In addition to hypoparathyroidism, lack of tooth enamel (enamel dystrophy), loss of hair (alopecia) and absence of pigment in areas of the skin (vitiligo) may also present. An eye disorder, corneal dystrophy (keratopathy), may also occur. There may be failure of sexual development, yeast infections of the mouth and nails (candidiasis), and the inability to properly absorb nutrients from food (malabsorption). Patients may develop liver disease or insulin- dependent diabetes as well as any combination of the various disorders. (For more information on this disorder, choose "APS type-1" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of Addison's disease is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Often a diagnosis is made incidentally during a routine exam when a blood test shows low levels of sodium or high levels of potassium. A diagnosis may be confirmed through a variety of specialized tests including the ACTH stimulation test, insulin-induced hypoglycemia test and x-ray examination.

The ACTH stimulation test measures the amount of cortisol in the blood. During this test, adrenocorticohormone (ACTH) is injected into the body, stimulating production of cortisol. If the test fails to stimulate adequate cortisol production, it indicates that the adrenal glands are damaged or not functioning properly.

The insulin-induced hypoglycemia test may be used to determine if the symptoms of Addison's disease are due to problems with the pituitary gland. This test measures blood sugar (glucose) levels before and after the injection of fast-acting insulin, which should lead to a drop in glucose and a rise in cortisol.

X-ray imaging techniques such as computed tomography (CT scan) of the abdomen may be taken to check the size of the adrenal glands and to detect other signs of disease such as calcification of the adrenal glands. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure.

Treatment
The treatment of Addison's disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Individuals with Addison's disease are treated by replacing the deficient steroid hormones (cortisol and aldosterone). Cortisol is replaced by the drug hydrocortisone and aldosterone is replaced by the drug fludrocortisone. The dosage of these drugs is different for each individual and the dosage may be increased during infection, trauma, surgery and other stressful situations to prevent an acute adrenal crisis. Some individuals may be encouraged to increase the salt intake in their diets.

An adrenal crisis demands immediate intravenous (injected directly into a blood vessel) administration of high-dose hydrocortisone and fluid (salt water) and electrolyte replacement; a short-term course of other drugs called vasopressors may be needed to maintain blood pressure. Affected individuals should carry a card or wear a tag stating that they have Addison's disease.

Investigational Therapies

Some individuals with Addison's disease may also be treated with androgen replacement therapy, specifically a drug called dehydroepiandrosterone (DHEA). Researchers have reported improvements in mood, fatigue and general psychological well-being among individuals with Addison's disease treated with DHEA replacement therapy. For women, androgen replacement therapy may also improve their sex drive and sexual satisfaction.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Addison's Disease Resources

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